Neglected Diseases
River Blindness: A Success Story
under Threat?
María-Gloria Basáñez*, Sébastien D. S. Pion, Thomas S. Churcher, Lutz P. Breitling, Mark P. Little, Michel Boussinesq
“T
he accomplishments of this Programme inspire
all of us in public health to dream big dreams. It
shows we can reach ‘impossible’ goals and lighten
the burden of millions of the world’s poorest people ... .”
These were the concluding words by former World Health
Organization Director-General Gro Harlem Brundtland
at the closure ceremony of the Onchocerciasis Control
Programme in West Africa (OCP) in December 2002 [1].
The success of the OCP is so undeniable and exemplary,
with 600,000 cases of blindness prevented, 18 million
children born in areas freed from the risk of blindness, and
25 million hectares of land safe for resettlement, that river
blindness is currently considered a disease of the past. This
perception nonetheless forgets that OCP covered, at most,
1,200,000 square kilometers to protect 30 million people in
11 countries, leaving a remaining 100 million people in areas
where active transmission of onchocerciasis still occurs. After
its 28-year fight OCP may have won a battle, but a much more
difficult task lies ahead before we can claim victory against
river blindness [2].
Etiology and Distribution
Human onchocerciasis is caused by the filarial parasitic
nematode Onchocerca volvulus. Adult worms (macrofilariae)
live in subcutaneous nodules and deeper worm bundles,
where fertilized females can produce, during an average of 10
years, millions of microfilariae responsible for the morbidity
associated with the infection. Ingested during a bloodmeal
by Simulium (black fly) vectors, microfilariae develop within
the fly to infective (L3) stages, that are then transmissible to
other people (Figure 1). Many simuliid species have been
incriminated to a greater or lesser degree in the transmission
of O. volvulus [3], their relative vectorial roles contributing
to shape diverse transmission patterns across endemic areas.
In Africa, the Simulium damnosum sensu lato (s.l.) species
complex, which includes approximately 60 cytoforms, is
responsible for more than 95 percent of onchocerciasis cases
globally [3,4]. In Latin America, S. ochraceum s.l., S. exiguum
s.l., S. metallicum s.l., and S. guianense s.l. are the main vectors,
respectively, in Mexico and Guatemala (about 360,000 people
at risk), Colombia and Ecuador (24,600), northern Venezuela
(104,500), and southern Venezuela and Brazil (20,000) [5,6].
O. volvulus is endemic in 27 sub-Saharan African countries,
the Yemen [7], and was imported through the slave trade
to six Latin American countries. Previous estimates have
placed the number of people infected worldwide at 18
million [7], 99 percent of them in Africa. Since then, the true
extent of the disease has been estimated by REMO (rapid
The Neglected Diseases section focuses attention either on a specific disease or
describes a novel strategy for approaching neglected health issues in general.
PLoS Medicine | www.plosmedicine.org
epidemiological mapping of onchocerciasis). Villages are
selected in each river basin according to appropriate criteria,
and levels of endemicity are assessed by onchocercal nodule
prevalence in adult host samples [8]. By 2005, more than
22,000 villages in Africa (outside the OCP area) had been
surveyed, allowing the identification of many new foci (Figure
2). The new infected populations thus found, together
with their demographic increase, certainly compensate for
the number of cases prevented by the OCP (where it was
estimated that roughly 3 million people were infected [7]).
Presently, it is estimated that 37 million people carry
O. volvulus, with 90 million at risk in Africa [9].
Clinical Manifestations and Pathogenesis
Onchocerciasis is better known as river blindness because
of the high prevalence of blindness in villages located along
fast-flowing rivers, where the vectors breed. Up to 500,000
cases of severe visual impairment (including visual field
reduction), and 270,000 of blindness have been attributed
to onchocerciasis [7], but, again, these figures certainly
underestimate the true magnitude of the problem. Ocular
lesions can involve all eye tissues, ranging from punctate
and sclerosing keratitis (anterior segment) to optic nerve
atrophy (posterior segment). Blindness incidence has
recently been shown to be associated with past microfilarial
load in individuals followed up within the OCP cohort [10],
confirming the progressive worsening of onchocercal eye
Funding: The authors received no specific funding for this article.
Competing Interests: The authors have declared that no competing interests exist.
Citation: Basáñez M-G, Pion SDS, Churcher TS, Breitling LP, Little MP, et al. (2006)
River blindness: A success story under threat? PLoS Med 3(9): e371. DOI: 10.1371/
journal.pmed.0030371
DOI: 10.1371/journal.pmed.0030371
Copyright: © 2006 Basáñez et al. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author
and source are credited.
Abbreviations: APOC, African Programme for Onchocerciasis Control; CDTI,
community-directed treatment with ivermectin; OCP, Onchocerciasis Control
Programme in West Africa; OEPA, Onchocerciasis Elimination Program for the
Americas; s.l., sensu lato (denotes a complex of simuliid sibling species)
María-Gloria Basáñez, Sébastien D. S. Pion, and Thomas S. Churcher are,
respectively, Senior Lecturer, post-doctoral research associate, and doctoral
student at the Department of Infectious Disease Epidemiology, and Mark P. Little is
Reader at the Department of Epidemiology and Public Health, Imperial College of
Science, Technology and Medicine, London, United Kingdom. Lutz P. Breitling is a
doctoral student at the Research Institute for Integrative and Comparative Biology,
University of Leeds, United Kingdom. Michel Boussinesq is Director of Research at
the Unité de recherche 024, Institut de Recherche pour le Développement, Paris,
France.
* To whom correspondence should be addressed. E-mail: m.basanez@imperial.
ac.uk
1454 September 2006 | Volume 3 | Issue 9 | e371
DOI: 10.1371/journal.pmed.0030371.g001

Figure 1. Life Cycle of O. volvulus

Mean dimensions of parasite stages are: Adult females, 35-70 cm × 400 µm; adult males, 2-4 cm × 150-200 µm; microfilariae, 250-360 × 5-9 µm; L1
larvae, 200 µm × 12 µm (front) and 20 µm (rear); L3, 440-700 × 20 µm. L1 larvae molt into L2, pre-infective larvae, and L2 into L3, infective larvae [5].
(Illustration: Giovanni Maki, derived from a CDC image at http://www.dpd.cdc.gov/dpdx/HTML/Filariasis.htm)

disease with parasite exposure (Figure 3A). Conventionally,
anterior chamber lesions had been attributed to a cascade of
inflammatory processes triggered by filarial products [11]. A
novel hypothesis proposes that the pro-inflammatory events
leading to increasing corneal opacity are stimulated not
only by the parasite itself, but also by its recently discovered
endosymbiotic Wolbachia bacteria, when released by dying
microfilariae [12,13]. By contrast, the pathogenesis of
retinal lesions, which may continue progressing despite
parasite clearance after chemotherapy, may result from
autoimmune processes elicited by cross-reactivity between
the O. volvulus antigen Ov39 and the human retinal antigen
hr44 [14].
Onchocerciasis also causes troublesome itching and
skin changes ranging from early, reactive lesions—acute
papular onchodermatitis, chronic papular onchodermatitis,
and lichenified onchodermatitis—to late changes such as
depigmentation and skin atrophy [15]. When limited to

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DOI: 10.1371/journal.pmed.0030371.g002
Figure 2. Distribution of Onchocerciasis Showing Current Status of Global Onchocerciasis Control
Red areas represent areas receiving ivermectin treatment. Yellow areas represent areas requiring further epidemiological surveys. The green area is
the area covered by the Onchocerciasis Control Programme in West Africa. Pink zones indicate the special intervention zones, i.e., previous OCP areas
receiving ivermectin and some vector control. Map redrawn from [53,75,76].
one limb, lichenified onchodermatitis is also called “sowda.”
Despite high skin microfilarial loads in endemic areas, most
patients present with subclinical or intermittent dermatitis
corresponding to acute papular onchodermatitis, with
little cellular attack against live microfilariae (generalized
onchocerciasis). Clinical lesions correspond to infiltrates
around dead or degenerating microfilariae surrounded
by macrophages, eosinophils, and neutrophils [16]. As in
the cornea, inflammation appears to be largely induced
by Wolbachia endobacterial products [13]. In generalized
onchocerciasis, the T helper cell type 1– and T helper cell
type 2–dependent effector reactions are suppressed by a
third arm of the T helper pathway, the T helper cell type 3,
or T regulatory cell type 1 [17]. Antigen-specific T regulatory
cell type 1 cells constitute a major source of interleukin 10,
leading to a downregulation of the immune system that
both prevents immune-mediated damage and facilitates
parasite survival [13]. By contrast, patients with severe or
hyperreactive skin lesions, such as lichenified onchodermatitis
or sowda, often present with low microfilarial loads. Their
lesions are due to repeated cycles of inflammation, eosinophil
and macrophage infiltration, and destruction of live and dead
microfilariae [18]. These different immune responses to the
parasite and ensuing clinical presentation may be influenced
by host genetic factors [19].
Onchocerciasis is also a systemic disease that is associated
with musculoskeletal pain, reduced body mass index, and
decreased work productivity. This may be due to the fact
that microfilariae can invade many tissues and organs,
and be found in blood and urine [5]. Involvement of
heavy microfilarial infection is also suspected in the onset
of epilepsy [20] and the hyposexual dwarfism known as
PLoS Medicine | www.plosmedicine.org 1456
Nakalanga syndrome [21]. A direct association between
microfilarial load and excess mortality of the human host has
been demonstrated recently [22] (Figure 3B).
Epidemiological Patterns
In contrast with some soil-transmitted helminths and
schistosomes, whose worm burdens typically peak in the
young, age-specific patterns of O. volvulus infection show
strong variation according to locality (microfilarial loads
can increase, decrease, or plateau with age), and may differ
markedly with host sex. Age- and sex-specific exposure,
endocrine factors, and parasite-induced immunosuppression
have been forwarded as possible explanations [23,24]. These
patterns have implications for O. volvulus population biology
and the design of control strategies.
The rationale behind the establishment of the OCP in
savannah areas of 11 West African countries was based on
the observation that there was a blinding savannah parasite
strain, transmitted by savannah members of S. damnosum
s.l., and a non-blinding forest strain, transmitted by forest
members. Cross-experimental infections had indicated
strong local adaptation and heterologous incompatibility,
suggesting that the existence of O. volvulus–S. damnosum
complexes could be responsible for the distinct distribution
and severity of onchocercal blindness [25]. DNA-based
methods confirmed an association between savannah and
forest parasite types with, respectively, severe and mild ocular
onchocerciasis [26]. In West African savannah, blindness
prevalence correlates positively with intensity of infection in
the community, a relationship rarely observed in West African
forest [27]. The geographic distribution of severe and mild
visual impairment is not, however, neatly confined to the
September 2006 | Volume 3 | Issue 9 | e371
savannah/forest divide. There are forest and forest–savannah
mosaic areas with high blindness prevalence [28] and
parasites distinct from those in West Africa, while in others,
parasites genetically indistinguishable from West African
savannah isolates are not associated with blindness [29,30].
The pathogenic differences of the various strains may be a
function of their relative Wolbachia load [31].
Disease Burden and Socioeconomic Consequences
The true burden of onchocerciasis has largely been
underestimated. Excess mortality of the blind, particularly
among males, may be considerable [32,33]. Even in
sighted individuals, high microfilarial load can negatively
affect a host’s life expectancy [22]. Parasite-induced
immunosuppression to specific and non-specific antigens
[34], impairment of the ability to fend off infections and
seroconvert successfully upon vaccinations [35], and
manifestations such as epilepsy possibly due to heavy infection
[20] may be partially responsible for excess mortality. It
is also well known that onchodermatitis and epilepsy are
associated with social stigmatization [36]. Onchocerciasis
is deemed responsible for the annual loss of approximately
1 million disability-adjusted life-years—healthy life-years
lost due to disability and mortality (more than half of
them due to skin disease [37])—which greatly reduces
income-generating capacity [38], incurs significant health
expenditures, and exerts, overall, an immensely negative
socioeconomic impact on the afflicted populations and their
land use [39]. Although not the only cause of depopulation
in some otherwise fertile West African valleys, onchocerciasis
prevented resettlement of these arable lands [40]. The
benefits accrued through onchocerciasis control programs
should be measured not only in terms of blindness cases
prevented and the cost-effectiveness of treatment [41,42], but
also in terms of number of deaths averted.
breastfeeding a child younger than one week old) once or
twice per year reduces morbidity and disability [46,47] and
lowers transmission [48,49]. Given the high initial endemicity
in some foci, annual regimes are not considered sufficient to
achieve local elimination of parasite populations [50], unless
very high therapeutic coverage (more than 80 percent of the
total population) is achieved for at least 25 years without loss
of treatment efficacy [51].
In Latin America, focal vector control was conducted in
Guatemala with some degree of success against the local
S. ochraceum s.l. vector [52], but was otherwise considered
impractical. The Onchocerciasis Elimination Program for
the Americas (OEPA) was initiated in 1993 as a regional
partnership to eliminate all morbidity from onchocerciasis
(and suppress its transmission wherever possible) in foci
of the six affected Latin American countries [53]. OEPA’s
strategy is currently based on biannual mass ivermectin
distribution, as it was considered that treatment every six
months would have a greater impact on transmission [54]
and female worm fecundity [55].
In 1995, the African Programme for Onchocerciasis
Control (APOC) was launched in order to cover the
remaining 19 African countries not protected under the
OCP umbrella [56]. (Three of them, Kenya, Rwanda, and
Mozambique, were found not to be endemic.) Since then,
APOC’s strategy has been based on annual ivermectin
distribution. The levels of geographic (percentage of

Onchocerciasis Control Strategies

The mainstay of onchocerciasis control is through
antivectorial and antiparasitic measures. The former
are directed against the black fly aquatic stages, and the
latter against the microfilariae. As yet there is no effective
macrofilaricidal drug that is safe for mass treatment. The OCP
initially implemented weekly larviciding of vector breeding
grounds, with the aim of interrupting transmission in the core
OCP area. After achieving this, elimination of the parasite
required abolishing vector sources for as long as microfilariae
remain in human skin. This duration was deemed to be
at least 14 years (considering the life expectancies of both
adult worms and microfilariae) [43]. In some parts of the
OCP area, children born after the initiation of vector control
proved to be uninfected [44]. In 1987, Merck took the
unprecedented decision to donate ivermectin (Mectizan),
an effective and safe microfilaricide, for as long as necessary
to eliminate onchocerciasis as a public health problem.
Following this commitment, regular ivermectin distribution by
mobile teams was introduced to complement vector control DOI: 10.1371/journal.pmed.0030371.g003
in some OCP areas, or as the sole intervention in others [45].
Ivermectin, given at the dose of 150 micrograms per kilogram Figure 3. The Incidence of Blindness and Excess Mortality Rate, by
of body weight, acts as a highly effective microfilaricide and Sex, Plotted against O. volvulus Microfilarial Load
inhibits microfilarial production by female worms for several Arithmetic mean of microfilarial counts from two skin snips, taken from
the right and left ileac crests, using a 2-millimeter Holth corneoscleral
months. Mass administration of ivermectin (to all those aged punch. (A) Blindness; (B) excess mortality rate. Error bars denote 95
five years or older, excluding pregnant women and those percent confidence intervals [10,22].

PLoS Medicine | www.plosmedicine.org 1457 September 2006 | Volume 3 | Issue 9 | e371

villages treated in an area) and therapeutic (percentage of
population treated in a village) coverage achieved by mobile
teams tended to be unsatisfactory, with little prospects of
sustainability. Instead, APOC has implemented, with great
success, the modality of community-directed treatment
with ivermectin (CDTI), by which communities themselves
appoint accountable local distributors [57]. By the end
of 2005, 400 million treatments had been supplied by the
Mectizan Donation Program, with an estimated 40 million
people living in 90,000 African villages being treated by nearly
300,000 community distributors throughout APOC projects.
The average cost per person treated, including volunteers’
time, is US$0.74, making CDTI highly cost-effective [9].
Besides, the cost per person treated as part of APOC
(not including the value of Mectizan) is nearly 8.5 times
cheaper than the cost per person protected, via vector
control, under the OCP [42]. In addition, the CDTI strategy
has empowered communities to such an extent that it is
currently being used as a platform for integrating other,
mainly chemotherapeutic community-based interventions
(such as vitamin A supplementation and albendazole for
lymphatic filariasis treatment). Integration with other control
programs may help maintain high coverage levels as clinical
symptoms of onchocerciasis subside [58]. However, in spite
of its impressive achievements in terms of coverage, and the
promising perspectives of combined community-directed
interventions, APOC has to face serious challenges in terms
of achieving its ultimate treatment goal of both long-term
sustainability and substantial permanent impact.
In those areas where onchocerciasis and loiasis (caused by
the filarial nematode Loa loa) are coendemic (mainly central
Africa), ivermectin treatment for O. volvulus in individuals with
high L. loa microfilaraemia can result in severe adverse events,
including fatal encephalopathy [59]. This has represented an
important setback to APOC’s expansion. Geostatistical models
are being developed to map the risk of heavy loiasis across
Africa [60], and treatment protocols will be tested aimed to
reduce L. loa microfilaraemia prior to ivermectin treatment.
Studies aimed at evaluating the sustainability of APOC-
sponsored projects have also revealed that communities do
not always support distributors adequately; the continued
commitment of distributors is often maintained because
of their involvement in other more “lucrative” activities,
such as immunization. Lack of resources makes supervision
difficult at the community and health facility levels, and many
obstacles must yet be overcome to integrate CDTI successfully
with other health activities [61].
These concerns raise questions as to how long APOC
should last. When launched, it was anticipated that APOC’s
duration would be 12 years (1995 through 2007). Since then,
a two-year phasing-out period has been added, and donors’
support secured until 2010. Presently, no decisions regarding
further extensions have been made, but, given the life cycles
of the parasite and its vector, APOC’s activities would likely
need to be sustained for at least 20 years to have a significant
and enduring impact [42].
Need for Other Effective Compounds against
O. volvulus
The increasing reliance of onchocerciasis control upon
ivermectin alone, and the absence of a real breakthrough in
vaccine development [62], have spurred research on other
PLoS Medicine | www.plosmedicine.org
compounds. Moxidectin has emerged as a highly efficacious
microfilaricide whose half-life in humans is longer than that
of ivermectin [63]; it may therefore suppress adult worm
fecundity for longer [63]. Its chemical structure is similar to
that of ivermectin, and, in animal models, it does not seem to
be truly macrofilaricidal [64].
Novel chemotherapeutic interventions could be based on
the use of antibiotics against the endosymbiotic bacteria, as
long-term depletion of Wolbachia impairs worm reproduction
and survival [65]. Daily treatment with 100 milligrams of
doxycycline for six weeks (or 200 milligrams daily for four
weeks) leads to an interruption of embryogenesis that lasts for
18 months or more [66]. However, the prolonged duration
of treatment, the various contraindications to antibiotics, and
the risk of inducing resistance in other pathogens make it
difficult to incorporate these regimens in mass chemotherapy
programs. Research on the efficacy of other antibiotics and
the shortest course of treatment that can effectively remove
the bacteria permanently may help overcome some of these
obstacles [67]. Alternatively, anti-Wolbachia therapy could
be used to treat selectively those individuals identified as
microfilaria-positive at the end of mass ivermectin distribution
in order to “mop up” areas where parasite elimination is
deemed feasible.
It is to be expected that the scaling up of all ivermectin-
reliant control programs (previous OCP countries and those
within APOC and OEPA) will impose selection pressures
on the parasite genome. Although no confirmed case of
ivermectin resistance has yet been identified, a phenotype
of suboptimal response to the drug has been reported in
localities in Ghana subjected to more than nine treatments
[68]. This phenomenon appears to be explained not by loss
of microfilaricidal efficacy, but by adult females resuming
reproductive activity earlier than expected. Evidence of
selection operating upon polymorphic loci (associated
with ivermectin resistance in veterinary nematodes) has
been documented by genetic analysis of worms obtained
from patients who had received six or more annual doses
in comparison to those who were ivermectin-naïve [69].
However, the definitive studies linking response phenotype
to parasite genotype with increasing treatment doses have yet
to be conducted. Mathematical models can help understand
parasite population biology processes that influence rates
of infection recrudescence [70,71] and the spread of alleles
favored by ivermectin-induced selection.
Modeling for Onchocerciasis Control
Onchocerciasis is one of the best examples in the history of
parasitic control in which intervention strategies have been
informed at all stages by computer simulation models. In
particular, ONCHOSIM, a computer program for modeling
onchocerciasis transmission and control, was developed
under the sponsorship of OCP for West African savannah
settings [72]. Other models pertain to transmission and
control in forest areas and Latin American foci [73]. The
key question of how long antifilarial treatment should be
administered depends on the anticipated goals and the
particular epidemiology of specific foci. If the objective is
elimination of onchocerciasis as a public health problem,
annual ivermectin administration in APOC countries will
constitute a successful strategy once the levels of infection in
the community are reduced below five to ten microfilariae
1458 September 2006 | Volume 3 | Issue 9 | e371
per skin snip, but this is unlikely to interrupt transmission
of O. volvulus in Africa [74]. Factors such as the intensity
and seasonality of transmission, the Onchocerca–Simulium
combination(s) present, the parasite distribution among
hosts, the density-dependent processes operating upon the
parasite’s life cycle, and the interaction of all these with
control interventions and their coverage will determine
the stability of the host–parasite system and our ability (or
inability) to push O. volvulus below possible transmission
breakpoints [70,71,73].
Conclusion
Neglect manifests itself in many guises. Financial and
political commitment are required not only to support the
control programs but also to fund the research necessary
to provide the tools to enable parasite elimination. The
spectacular success of the OCP has pushed onchocerciasis
down to the bottom of the health research agenda at a time
when consolidating its achievements and demonstrating
long-term success in APOC and OEPA are of utmost
importance. Priority should be given to the development
of tools for improved diagnosis (detection of skin
microfilariae will lose sensitivity as control progresses, and
parasite antigen tests have proved elusive), efficacious
killing of adult worms, early detection of potential loss of
drug efficacy and associated parasite genetic changes, and
better understanding of the impact of chemotherapeutic
interventions upon the population biology of O. volvulus. At
present, the prospect of indefinite ivermectin distribution
risks the development of anthelmintic resistance and tempts
public and donor fatigue.

Supporting Information
Text S1. Translation of the Article into German
Found at DOI: 10.1371/journal.pmed.0030371.sd001 (60 KB DOC).
Text S2. Translation of the Article into French
Found at DOI: 10.1371/journal.pmed.0030371.sd002 (122 KB DOC).
Text S3. Translation of the Article into Spanish
Found at DOI: 10.1371/journal.pmed.0030371.sd003 (100 KB DOC).
Acknowledgments
The ideas discussed here have benefited from the support to the
authors over the years by a number of research-funding bodies such
as the Wellcome Trust (MGB), the Medical Research Council UK
(MGB and TSC), the Fondations pour la Recherche Médicale and
Singer-Polignac, France (SDSP), the River Blindness Foundation,
and the UNICEF/UNDP/World Bank/WHO Special Programme for
Research and Training in Tropical Diseases (MB).
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